Comparison of peak wall stress and peak wall rupture index in ruptured and asymptomatic intact abdominal aortic aneurysms.

BACKGROUND: Previous studies have suggested that finite element analysis (FEA) can estimate the rupture risk of an abdominal aortic aneurysm (AAA); however, the value of biomechanical estimates over measurement of AAA diameter alone remains unclear. This study aimed to compare peak wall stress (PWS) and peak wall rupture index (PWRI) in participants with ruptured and asymptomatic intact AAAs. METHODS: The reproducibility of semiautomated methods for estimating aortic PWS and PWRI from CT images was assessed. PWS and PWRI were estimated in people with ruptured AAAs and those with asymptomatic intact AAAs matched by orthogonal diameter on a 1 : 2 basis. Spearman's correlation coefficient was used to assess the association between PWS or PWRI and AAA diameter. Independent associations between PWS or PWRI and AAA rupture were identified by means of logistic regression analyses. RESULTS: Twenty individuals were included in the analysis of reproducibility. The main analysis included 50 patients with an intact AAA and 25 with a ruptured AAA. Median orthogonal diameter was similar in ruptured and intact AAAs (82·3 (i.q.r. 73·5-92·0) versus 81·0 (73·2-92·4) mm respectively; P = 0·906). Median PWS values were 286·8 (220·2-329·6) and 245·8 (215·2-302·3) kPa respectively (P = 0·192). There was no significant difference in PWRI between the two groups (P = 0·982). PWS and PWRI correlated positively with orthogonal diameter (both P < 0·001). Participants with high PWS, but not PWRI, were more likely to have a ruptured AAA after adjusting for potential confounders (odds ratio 5·84, 95 per cent c.i. 1·22 to 27·95; P = 0·027). This association was not maintained in all sensitivity analyses. CONCLUSION: High aortic PWS had an inconsistent association with greater odds of aneurysm rupture in patients with a large AAA.

Effects of quercetin on exercise performance, physical activity and blood supply in a novel model of sustained hind-limb ischaemia.

BACKGROUND: There are currently few effective drugs to treat the leg symptoms of peripheral arterial disease (PAD). Previous studies have suggested that the nutraceutical, quercetin, can improve exercise performance and reduce pain sensitivity in healthy mice and improve blood supply in a rodent model of acute hind-limb ischaemia. These models may not be relevant to people with PAD. The aim of this study was to examine the effect of quercetin on exercise performance, physical activity and blood supply in a novel mouse model of sustained hind-limb ischaemia. METHODS: Hind-limb ischaemia was induced in 6-month-old male apolipoprotein E-deficient mice using a novel two-stage surgical procedure. Five days after induction of ischaemia, mice were allocated to commence dietary quercetin or a control diet for 4 weeks. The primary outcome was exercise performance evaluated using a treadmill test. Other outcomes included physical activity, estimated by an open field test, and hind-limb blood supply, assessed by laser Doppler monitoring. RESULTS: A sustained reduction in relative limb blood supply (P < 0.001) was achieved consistently in all 48 mice before allocation to a control (n = 24) or quercetin (n = 24) diet. Quercetin did not improve exercise performance (P = 0.785), physical activity (P = 0.151) or relative limb blood supply (P = 0.954) over the 4-week assessment period. CONCLUSION: These data suggest that quercetin does not improve exercise performance, physical activity or limb blood supply in mice with sustained hind-limb ischaemia, and therefore is unlikely be an effective treatment for PAD.

Meta-analyses of randomized controlled trials reporting the effect of home foot temperature monitoring, patient education or offloading footwear on the incidence of diabetes-related foot ulcers.

AIM: The aim of this study was to perform an up-to-date systematic review and meta-analysis of randomized controlled trials (RCTs) examining the efficacy of home foot temperature monitoring, patient education and offloading footwear in reducing the incidence of diabetes-related foot ulcers. METHODS: A literature search was performed using MEDLINE, PubMed, CINAHL, Scopus and Cochrane databases to identify relevant original studies. Meta-analyses were performed using intention-to-treat principals for worst (main analysis) and best (sub-analysis) case scenarios. Leave-one-out sensitivity analyses were used to assess the consistency of findings. RESULTS: Of 7575 unique records, 17 RCTs involving 2729 participants were included. Four tested home foot temperature monitoring (n = 468), six examined patient education (n = 823) and seven assessed offloading footwear (n = 1438). Participants' who performed home foot temperature monitoring [odds ratio (OR) 0.51, 95% confidence interval (CI) 0.31 to 0.84; n = 468] and those provided offloading footwear (OR 0.48, 95% CI 0.29 to 0.80; n = 1438) were less likely to develop a diabetes-related foot ulcer. Patient education programmes did not significantly reduce diabetes-related foot ulcer incidence (OR 0.59, 95% CI 0.29 to 1.20; n = 823). Sensitivity analyses suggested that offloading footwear findings were consistent, but home foot temperature findings were dependent on the individual inclusion of one trial. All RCTs had either high or unclear risk of bias. CONCLUSION: This meta-analysis suggests that offloading footwear is effective in reducing the incidence of diabetes-related foot ulcers. Home foot temperature monitoring also appears beneficial but larger trials are needed (PROSPERO registration no.: CRD42019135226).

Lack of an effective drug therapy for abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) rupture is a common cause of death in adults. Current AAA treatment is by open surgical or endovascular aneurysm repair. Rodent model and human epidemiology, and genetic and observational studies over the last few decades have highlighted the potential of a number of drug therapies, including medications that lower blood pressure, correct dyslipidaemia, or inhibit thrombosis, inflammation or matrix remodelling, as approaches to managing small AAA. This review summarizes prior AAA pathogenesis data from animal and human studies aimed at identifying targets for the development of drug therapies. The review also systematically assesses past randomized placebo-controlled drug trials in patients with small AAAs. Eleven previously published randomized-controlled clinical trials testing different drug therapies aimed at slowing AAA progression were identified. Five of the trials tested antibiotics and three trials assessed medications that lower blood pressure. Meta-analyses of these trials suggested that neither of these approaches limit AAA growth. Allocation to blood pressure-lowering medication was associated with a small reduction in AAA rupture or repair, compared to placebo (relative risk 0.94, 95% confidence intervals 0.89, 1.00, P = 0.047). Three further trials assessed the effect of a mast cell inhibitor, fibrate or platelet aggregation inhibition and reported no effect on AAA growth or clinical events. Past trials were noted to have a number of design issues, particularly small sample sizes and limited follow-up. Much larger trials are needed to properly test potential therapeutic approaches if a convincingly effective medical therapy for AAA is to be identified.

Meta-analysis of clinical trials examining the benefit of structured home exercise in patients with peripheral artery disease.

BACKGROUND: Supervised exercise is recommended for the management of peripheral artery disease (PAD); however, the uptake is limited. Structured home exercise programmes may be more feasible, but their effectiveness is unclear. This systematic review and meta-analysis examined the benefit of structured home exercise programmes for treating PAD in comparison to controls not receiving an exercise programme. METHODS: A literature search was conducted to identify RCTs comparing structured home exercise with controls not receiving an exercise programme among patients with PAD. To be included, studies had to report outcomes from treadmill or corridor walking tests, or objective assessment of physical activity. Inverse variance-weighted meta-analysis was performed to compare changes in maximum walking distance and intermittent claudication onset distance in treadmill tests, walking distance during a 6-min walking test, and physical activity measured using a pedometer or accelerometer. Summarized results are presented in terms of standard deviation differences. RESULTS: Eleven randomized trials involving 807 patients were included. Follow-up ranged from 2 to 24 months; only one trial included follow-up beyond 12 months. Meta-analyses showed that structured home exercise programmes led to significant improvements in maximum walking distance (mean difference (MD) 0·32, 95 per cent c.i. 0·15 to 0·50; P < 0·001), intermittent claudication onset distance (MD 0·45, 0·27 to 0·62; P < 0·001), walking distance in a 6-min walking test (MD 0·28, 0·09 to 0·47; P = 0·004) and physical activity (MD 0·27, 0·11 to 0·43; P = 0·001). CONCLUSION: This meta-analysis suggests that structured home exercise programmes are effective at improving walking performance and physical activity in the short term for patients with PAD.

Risk of major amputation in patients with intermittent claudication undergoing early revascularization.

BACKGROUND: Revascularization is being used increasingly for the treatment of intermittent claudication and yet few studies have reported the long-term outcomes of this strategy. The aim of this study was to compare the long-term outcome of patients with intermittent claudication who underwent revascularization compared with a group initially treated without revascularization. METHODS: Patients with symptoms of intermittent claudication and a diagnosis of peripheral arterial disease were recruited from outpatient clinics at three hospitals in Queensland, Australia. Based on variation in the practices of different vascular specialists, patients were either treated by early revascularization or received initial conservative treatment. Patients were followed in outpatient clinics using linked hospital admission record data. The primary outcome was the requirement for major amputation. Kaplan-Meier curves, Cox regression and competing risks analyses were used to compare major amputation rates. RESULTS: Some 456 patients were recruited; 178 (39·0 per cent) underwent early revascularization and 278 (61·0 per cent) had initial conservative treatment. Patients were followed for a mean(s.d.) of 5·00(3·37) years. The estimated 5-year major amputation rate was 6·2 and 0·7 per cent in patients undergoing early revascularization and initial conservative treatment respectively (P = 0·003). Early revascularization was associated with an increased requirement for major amputation in models adjusted for other risk factors (relative risk 5·40 to 4·22 in different models). CONCLUSION: Patients presenting with intermittent claudication who underwent early revascularization appeared to be at higher risk of amputation than those who had initial conservative treatment.

Meta-analysis of the association between peripheral artery disease and growth of abdominal aortic aneurysms.

BACKGROUND: The role of atherosclerosis in the pathogenesis of abdominal aortic aneurysm (AAA) is controversial. Atherosclerosis-associated peripheral artery disease (PAD) has been reported to be a risk factor for AAA in population screening studies; its relationship with AAA growth is controversial. METHODS: A systematic search of MEDLINE, Scopus, CINAHL and the Cochrane Central Register of Controlled Trials was conducted in April 2016 and repeated in January 2017. Databases were screened for studies reporting AAA growth rates in patients with, and without PAD. The included studies underwent quality assessment and, where possible, were included in the meta-analysis. A subgroup analysis was performed, including only studies that adjusted for confounding factors. RESULTS: Seventeen studies, including a total of 4873 patients, met the review entry criteria. Data from 15 studies were included in the meta-analysis. There was marked heterogeneity in study design, methodology and statistical analyses used. In the main analysis, PAD was associated with reduced AAA growth (mean difference - 0·13, 95 per cent c.i. -0·27 to -0·00; P = 0·04). However, statistical significance was not maintained in sensitivity analysis. In a subanalysis that included only data adjusted for other risk factors, no significant association between PAD and AAA growth was found (mean difference -0·11, -0·23 to 0·00; P = 0·05). CONCLUSION: This systematic review suggests that currently reported studies demonstrate no robust and consistent association between PAD and reduced AAA growth.

Systematic Review and Meta-Analysis of the Association Between C-Reactive Protein and Major Cardiovascular Events in Patients with Peripheral Artery Disease.

BACKGROUND: Patients with peripheral artery disease (PAD) are at substantial risk of cardiovascular events. There is interest in using blood markers, such as C-reactive protein (CRP), to monitor prognosis and treatment efficacy in PAD patients. The aim of this meta-analysis was to assess the association between CRP and major cardiovascular events in PAD patients. METHOD: Studies evaluating the association between CRP and major cardiovascular events (myocardial infarction, stroke, cardiac revascularisation and mortality) were identified using MEDLINE and the Cochrane library. Studies that did not include participants with PAD, measure CRP, or follow-up patients for cardiovascular events were excluded. Meta-analyses of published adjusted hazard ratios (HR) were conducted using an inverse variance-weighted random effects model, and heterogeneity was assessed with the I2 index. RESULTS: A total of 16 studies involving 5041 participants met the inclusion criteria for the systematic review. Eight studies were included in the meta-analyses. Summary effect estimates were reported as HR comparing higher and lower quantiles, and HR per unit increase in logeCRP. PAD patients with higher CRP had a significantly greater risk of major cardiovascular events compared with those with lower CRP (HR 2.26, 95% CI 1.65-3.09, p < 0.001). The HR for major cardiovascular events was 1.38 (95% CI 1.16-1.63, p < 0.001) per unit increase in logeCRP. CONCLUSIONS: The present findings suggest that high circulating CRP is predictive of major cardiovascular events in PAD patients.

Assessment and validation of a novel angiographic scoring system for peripheral artery disease.

BACKGROUND: Angiography is used routinely in the assessment of lower-limb arteries, but there are few well validated angiographic scoring systems. The aim of this study was to develop and validate a novel angiographic scoring system for peripheral artery disease. METHODS: An angiographic scoring system (the ANGIO score) was developed and applied to a sample of patients from a single vascular surgical department who underwent CT angiography of the lower limbs. The reproducibility of the ANGIO score was compared with those of the Bollinger and Trans-Atlantic inter-Society Consensus (TASC) IIb systems in a series of randomly selected patients. Associations between the ANGIO score and lower-limb ischaemia, as measured by the ankle : brachial pressure index (ABPI), and outcome events (major lower-limb amputations and cardiovascular events - myocardial infarction, stroke and cardiovascular death) were assessed. RESULTS: Some 256 patients undergoing CT angiography were included. The interobserver reproducibility of the ANGIO score was better than that of the other scoring systems examined (κ = 0·90, P = 0·002). There was a negative correlation between the ANGIO score and ABPI (ρ = -0·33, P = 0·008). A higher ANGIO score was associated with an increased risk of major lower-limb amputation (hazard ratio (HR) for highest versus lowest tertile 9·30, 95 per cent c.i. 1·95 to 44·38; P = 0·005) and cardiovascular events (HR 2·73, 1·31 to 5·70; P = 0·007) following adjustment for established risk factors. CONCLUSION: The ANGIO score provided a reproducible and valid assessment of the severity of lower-limb ischaemia and risk of major amputation and cardiovascular events in these patients with peripheral artery disease.

Reported Amount of Salt Added to Food Is Associated with Increased All-Cause and Cancer-Related Mortality in Older Men in a Prospective Cohort Study.

BACKGROUND: The effect of dietary salt intake on important population outcomes such as mortality is controversial. The aim of this study was to examine the association between the dietary habit of adding salt to food and mortality in older men. Design, participants, setting and measurements: A risk factor questionnaire which contained a question about the dietary habit of adding salt to food was completed by 11742 community recruited older men between 1996 and 1999. The men were followed by means of the Western Australia Data Linkage System until November 30th 2010. Deaths due to cardiovascular diseases and cancers were identified using ICD-10 codes in the ranges I00-I99 and C00-D48, respectively. The association between the frequencies of adding salt to food and mortality was assessed using Kaplan Meier estimates and Cox proportional hazard analysis. RESULTS: Median follow-up for survivors was 12.5 years (inter-quartile range 8.3-13.2 years). A total of 5399 deaths occurred of which the primary cause registered was cancer and cardiovascular disease in 1962 (36.3%) and 1835 (34.0%) men, respectively. The reported frequency of adding salt to food was strongly positively associated with all-cause (p<0.001), cancer-related (p<0.001) but not cardiovascular-related (p=0.649) mortality. Men reporting adding salt to their food always had a 1.12-fold (95% CI 1.05-1.20, p<0.001) and a 1.20-fold (95% CI 1.07-1.34, p=0.001) increased risk of all-cause and cancer-related mortality, respectively, after adjusting for other risk factors. Men reporting adding salt to their food sometimes had a 1.16-fold (95% CI 1.04-1.29, p=0.007) increased risk of cancer-related mortality after adjusting for other risk factors. CONCLUSION: A history of adding salt to food is associated with increased cancer-related mortality in older men.

Plasma Low-density Lipoprotein Receptor-related Protein 1 Concentration is not Associated with Human Abdominal Aortic Aneurysm Presence.

OBJECTIVE/BACKGROUND: Recent genetic data suggest that a polymorphism of LRP1 is an independent risk factor for abdominal aortic aneurysm (AAA). The aims of this study were to assess whether plasma and aortic concentrations of low-density lipoprotein receptor-related protein 1 (LRP1) are associated with AAA, and to investigate the possible relevance of LRP1 to AAA pathophysiology. METHODS: Three analyses were conducted. First, plasma LRP1 concentrations were measured in community-dwelling men with and without AAA (n = 189 and n = 309, respectively) using enzyme-linked immunosorbent assay. Second, Western blotting analyses were employed to compare the expression of LRP1 protein in aortic biopsies collected from patients with AAA and nonaneurysmal postmortem donors (n = 6/group). Finally, the effect of in vitro LRP1 blockade on matrix metalloprotease 9 (MMP9) clearance by vascular smooth muscle cells was assessed by zymography. RESULTS: Plasma LRP1 concentrations did not differ between groups of men with and without AAA (median concentration 4.56 µg/mL [interquartile range {IQR} (3.39-5.96)] and 4.43 µg/mL [IQR 3.44-5.84], respectively; p = .48), and were not associated with AAA after adjusting for other risk factors (odds ratio 1.10 [95% confidence interval: 0.91-1.32]; p = 0.35). In contrast, LRP1 expression was approximately 3.4-fold lower in aortic biopsies recovered from patients with AAA compared with controls (median [IQR] expression 1.72 [0.94-3.14] and 5.91 [4.63-6.94] relative density units, respectively; p < .01). In vitro LRP1 blockade significantly reduced the ability of vascular smooth muscle cells to internalize extracellular MMP9. CONCLUSIONS: These data suggest that aortic but not circulating LRP1 is downregulated in patients with AAA and indicates a possible role for this protein in clearing an aneurysm-relevant ligand.

Meta-analysis of peak wall stress in ruptured, symptomatic and intact abdominal aortic aneurysms.

BACKGROUND: Abdominal aortic aneurysm (AAA) is an important cause of sudden death; however, there are currently incomplete means to predict the risk of AAA rupture. AAA peak wall stress (PWS) can be estimated using finite element analysis (FEA) methods from computed tomography (CT) scans. The question is whether AAA PWS can predict AAA rupture. The aim of this systematic review was to compare PWS in patients with ruptured and intact AAA. METHODS: The MEDLINE database was searched on 25 May 2013. Case-control studies assessing PWS in asymptomatic intact, and acutely symptomatic or ruptured AAA from CT scans using FEA were included. Data were extracted independently. A random-effects model was used to calculate standard mean differences (SMDs) for PWS measurements. RESULTS: Nine studies assessing 348 individuals were identified and used in the meta-analysis. Results from 204 asymptomatic intact and 144 symptomatic or ruptured AAAs showed that PWS was significantly greater in the symptomatic/ ruptured AAAs compared with the asymptomatic intact AAAs (SMD 0·95, 95 per cent confidence interval 0·71 to 1·18; P < 0·001). The findings remained significant after adjustment for mean systolic blood pressure, standardized at 120 mmHg (SMD 0·68, 0·39 to 0·96; P < 0·001). Minimal heterogeneity between studies was noted (I(2) = 0 per cent). CONCLUSION: This study suggests that PWS is greater in symptomatic or ruptured AAA than in asymptomatic intact AAA.

Immune responses directed at egg proteins during experimental infection with the liver fluke Fasciola hepatica.

Fasciola hepatica is responsible for human disease and economic livestock loss on a global scale. Unlike the well characterized schistosomes, only the adult and juvenile stages of F. hepatica are implicated in disease, whereas the freely voided egg is not thought to contribute to host-parasite interactions. We investigated specific immune responses to soluble F. hepatica egg proteins (SFHEP), during a 14-week experimental infection, demonstrating significant increases in anti-SFHEP IgG1 (P = 0.001), transforming growth factor beta-1 (P = 0.008) and IL-10 (P < 0.001) titres at the onset of egg production. Western blot analysis of soluble SFHEP demonstrates that protein bands migrating at 61.6, 54.8 and 44 kDa become sero-reactive before the appearance of eggs within host faeces. Therefore, expression of some egg-associated proteins indicates progression to chronic disease. Antigenic bands were investigated through mass spectrometry, identifying a protein disulphide isomerase (PDI) (61.6 kDa), an enolase and ferritin-related proteins (54.8 kDa), and a cocktail of dehydrogenases (44 kDa). Biochemical analysis of egg secretions reveals proteolytic activity, which increases over time, indicating that proteases may be continually secreted during the course of egg maturation. The implications of egg-specific immune responses and proteolytic secretions are further discussed.

Challenges, current status and future perspectives of proteomics in improving understanding, diagnosis and treatment of vascular disease.

Technical advances have seen the rapid adoption of genomics and multiplex genetic polymorphism identification to research on vascular diseases. The utilization of proteomics for the study of vascular diseases has been limited by comparison. In this review we outline currently available proteomics techniques, the challenges to using these approaches and modifications which may improve the utilization of proteomics in the study of vascular diseases.